Twenty-eight million Americans suffer from hearing impairment. By age 80 about half the population has age-related hearing loss (presbycusis). While some degree of presbycusis can be ascribed to environmental exposures, a significant fraction is genetically determined. To understand the etiology of age-related hearing impairment it is necessary to understand both the molecular physiology of hearing and the molecular pathology of hearing loss. Identification and characterization of the genes that contribute to the hearing process are required to accomplish this goal. Mutations in the gamma-actin gene cause progressive sensorineural hearing loss that resembles presbycusis except for an earlier age of onset. It is somewhat surprising for mutations in such a ubiquitously expressed and highly conserved gene, to be associated with no other observed symptoms, suggesting very specific functions for gamma-actin in the ear. This study is designed to characterize those specific functions and to determine how known mutations in the gene encoding this protein affect its role in hearing. Both biochemical characterization and in vivo approaches will be used to achieve the goals. The specific role that gamma-actin plays in the ear will be examined using in situ localization of the protein and transient expression of the gamma-actin in cochlear and vestibular hair cells. Animal models with the mutations will be created and characterized. Studies of cell cultures expressing the normal and mutant proteins will be undertaken. A series of biochemical tests to determine the effect of each mutation on specific actin functions will examine the effect of the mutation on filament formation, cross-linking and myosin movement. Because we do not know how prevalent gamma-actin mutations are as the cause of hearing loss, additional families will be sought. These studies will help us to understand the role of gamma-actin in maintaining homeostasis in the ear and may thereby lead to a better understanding of the common and distressing phenomenon of age-related hearing impairment known as "presbycusis".